1. Field of the Invention
The present invention relates to a process of preparing biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester. The invention further relates to processes of preparing a crystalline freebase of this ester. The invention also relates to a process of preparing an intermediate useful in the synthesis of the ester and the crystalline freebase.
2. State of the Art
U.S. Pat. No. 7,228,657 to Mammen et al. discloses novel biphenyl compounds that are expected to be useful for treating pulmonary disorders such as chronic obstructive pulmonary disease and asthma. In particular, the compound biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}-ethyl)piperidin-4-yl ester is specifically described in this application as possessing muscarinic receptor antagonist or anticholinergic activity, and is represented by formula I:
The compound of formula I is synthesized from the compound 8, which is described as being prepared from the oxidation of 2-(benzylmethylamino)ethanol to the aldehyde intermediate followed by reductive amination with biphenyl-2-yl-carbamic acid piperidin-4-yl ester and debenzylation:
However, while this procedure performs well on small scale, the aldehyde intermediate is difficult to scale up due to its instability, and low yields were typically observed.
Thus, a need exists for an efficient process of preparing compound 8 as a pure material with high chemical purity and good overall yield, without having to isolate intermediates. This invention addresses those needs.
Therapeutic agents useful for treating pulmonary or respiratory disorders are advantageously administered directly into the respiratory tract by inhalation. In this regard, several types of pharmaceutical inhalation devices have been developed for administering therapeutic agents by inhalation including dry powder inhalers, metered-dose inhalers, and nebulizer inhalers. When preparing pharmaceutical compositions and formulations for use in such devices, it is highly desirable to have a crystalline form of the therapeutic agent that is neither hygroscopic nor deliquescent and which has a relatively high melting point thereby allowing the material to be micronized without significant decomposition.
A crystalline diphosphate of the compound of formula I has been reported in U.S. Pat. No. 7,700,777 to Axt et al, and a crystalline freebase (identified as Form III) is described in U.S. Patent Application Publication No. 2011/0015163 to Woollham. All of the aforementioned disclosures are incorporated herein by reference.
The compound of formula I is described as being prepared by reacting compound 8 with 4-carboxybenzaldehyde to form the aldehyde core 10:
which is then isolated prior to being combined with isonipicotamide in the presence of a reducing agent to form the compound of formula I. The crystalline diphosphate is prepared by contacting the separated and purified compound of formula I with phosphoric acid. The crystalline freebase (Form III) can then be prepared from the crystalline diphosphate.
A need also exists for an efficient process of preparing the crystalline freebase (Form III). It is desirable to develop a process that does not first require preparation of the crystalline diphosphate. This invention addresses those needs.